RESUMO
BACKGROUND: Tumor hypoxia is marked by enhanced expression of hypoxia-inducible factor-alpha (HIF-1alpha) and glucose transporter-1 (Glut-1). Hypoxic conditions have also been associated with overexpression of angiogenic factors, such as leptin. The aim of our study was to analyze the relationships between hypoxia markers HIF-1alpha, Glut-1, leptin, leptin receptor (ObR) and other breast cancer biomarkers in primary and metastatic breast cancer in patients treated or untreated with preoperative chemotherapy. METHODS: The expression of different biomarkers was examined by immunohistochemistry in 116 primary breast cancers and 65 lymph node metastases. Forty five of these samples were obtained form patients who received preoperative chemotherapy and 71 from untreated patients. RESULTS: In primary tumors without preoperative chemotherapy, HIF-1alpha and Glut-1 were positively correlated (p = 0.02, r = 0.437). HIF-1alpha in primary and metastatic tumors without preoperative therapy positively correlated with leptin (p < 0.0001, r = 0.532; p = 0.013, r = 0.533, respectively) and ObR (p = 0.002, r = 0.319; p = 0.083, r = 0.387, respectively). Hypoxia markers HIF-1alpha and Glut-1 were negatively associated with estrogen receptor alpha (ERalpha) and positively correlated with estrogen receptor beta (ERbeta). In this group of tumors, a positive correlation between Glut-1 and proliferation marker Ki-67 (p = 0.017, r = 0.433) was noted. The associations between HIF-1alpha and Glut-1, HIF-1alpha and leptin, HIF-1alpha and ERalpha as well as Glut-1 and ERbeta were lost following preoperative chemotherapy. CONCLUSIONS: Intratumoral hypoxia in breast cancer is marked by coordinated expression of such markers as HIF-1alpha, Glut-1, leptin and ObR. The relationships among these proteins can be altered by preoperative chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Neoplasias da Mama/tratamento farmacológico , Transportador de Glucose Tipo 1/análise , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Leptina/análise , Receptores de Estrogênio/análise , Receptores para Leptina/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/secundário , Hipóxia Celular , Quimioterapia Adjuvante , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67/análise , Metástase Linfática , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
During carcinogenesis, loss of intracellular cohesion is observed among cancer cells with altered expression of such adhesion molecules as E-cadherin and beta-catenin, and aberrant expression and cellular location of intercellular gap junction proteins-connexins. The aim of this study was to evaluate immunohistochemically the expression and relationship between E-cadherin and beta-catenin, and the connexins Cx26 and Cx43 in 86 endometrioid adenocarcinomas. The aberrant cytoplasmic translocation of the studied proteins was a predominant finding, whereas only a minority of cases showed normal, nuclear beta-catenin labeling or membranous distribution of the remaining molecules. E-cadherin was positively and significantly associated with beta-catenin (P=0.001, r=0.366), as was Cx26 with Cx43 (P<0.001, r=0.719), E-cadherin with Cx26 (P<0.001, r=0.413), and E-cadherin and Cx43 (P<0.001, r=0.434) in all cancers. A subgroup of endometrioid adenocarcinomas (FIGO IB+II) exclusively showed a positive significant association between the expression of beta-catenin and Cx26 (P=0.038, r=0.339). In addition, there were significantly more beta-catenin-positive carcinomas among superficially spreading cancers (FIGO IA) than among deeper invading neoplasms (FIGO IB+II) (P=0.056). The altered location of the studied proteins indicates impairment of their physiological functions. In particular, normal membranous distribution of E-cadherin and connexins is lost and replaced by abnormal cytoplasmic accumulation in most cancers, and thus intercellular ties are expected to be weakened and loosened as a consequence. In contrast, the lack of relationship between beta-catenin and connexins, E-cadherin seems to be closely associated with the expression of Cx26 and Cx43 in endometrioid adenocarcinomas.
Assuntos
Caderinas/metabolismo , Carcinoma Endometrioide/patologia , Conexina 43/metabolismo , Conexinas/metabolismo , Neoplasias do Endométrio/patologia , beta Catenina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/metabolismo , Conexina 26 , Neoplasias do Endométrio/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estatísticas não ParamétricasRESUMO
UNLABELLED: The aim of this study was the assessment of expression and location of CX32 and CX43 in colorectal adenomas and carcinomas as well as analysis of expression of these proteins in association with clinical and pathological features of tumors and evaluation of mutual relationships between CX32 and CX43. PATIENTS AND METHODS: The study included 151 primary colorectal carcinoma and 71 colorectal adenomas. The control group comprised 30 colon samples. Connexins were detected with immunohistochemistry. RESULTS: There was a lack of membranous distribution of connexins or a shift from moderately membranous immunoreactivity to predominantly cytoplasmic accumulation of CX32 and CX43 in studied colon tumors. Mentioned alterations were found in adenomas and augmented in cancer. Expression of Cx32 was significantly associated with grading of colorectal cancer, implicating a role of intracellular CX32 in regulation of tumor growth and differentiation. A strong correlation was present between CX32 and CX43 in node-positive cases and absent from node-negative ones. CONCLUSION: To our knowledge, our study is the first illustration for a gradual loss of functional gap junctions within progression of colorectal neoplasia. An intracellular location of connexins, the site of their common and the most frequent detection within cancer cells in our study may be of significance. Independently of its role in functional gap-junctions, cytoplasmic CX32 could be involved in cancer differentiation, resulting in a higher rate of CX32 positive moderately differentiated tumors (G3) than poorly differentiated CX32-positive ones (G3).
Assuntos
Adenocarcinoma/metabolismo , Adenoma/metabolismo , Neoplasias Colorretais/metabolismo , Conexina 43/metabolismo , Conexinas/metabolismo , Junções Comunicantes/metabolismo , Adenocarcinoma/secundário , Adenoma/patologia , Biomarcadores Tumorais/metabolismo , Membrana Celular/metabolismo , Neoplasias Colorretais/patologia , Citoplasma/metabolismo , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Linfonodos/metabolismo , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Proteína beta-1 de Junções ComunicantesRESUMO
BACKGROUND: Insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) belong to a group of hypoxia related proteins. IGF-I induces expression of VEGF and decomposes wild type p53 in cancer cell lines. The goal of our study was to evaluate serum IGF-I, VEGF and p53 with respect to overall and disease free survival of patients with colorectal cancer (CRC) patients compared with healthy volunteers. METHODS: Preoperative blood samples from 125 patients with CRC and 16 healthy volunteers were examined using ELISA for serum IGF-I, p53 and VEGF concentrations. RESULTS: Concentrations of p53 and VEGF were significantly higher in CRC patients than in controls (p<0.0006 and p<0.0001, respectively). IGF-I was not statistically different between both groups. Serum IGF-I showed negative correlation with p53 in CRC patients (p<0.04, r=-0.193). IGF-I and VEGF showed negative correlation in poorly differentiated cancers (G3) (p<0.03, r=-0.339). Patients with VEGF concentrations that were above average for the cancer population survived for a shorter period of time (p=0.065 in evaluation of overall survival and 0.071 in estimation of disease-free survival during a 3-year follow-up) compared with patients with serum VEGF lower than the highest values seen in controls. CONCLUSIONS: Comparisons between serum IGF-I and p53 appear to confirm the metabolism of p53 by IGF-I. Serum VEGF showed prognostic significance in our study. Serum concentrations of IGF-I and VEGF did not show positive correlation, as expected due to IGF-I induction of VEGF in malignant colon cell lines.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/diagnóstico , Fator de Crescimento Insulin-Like I/análise , Período Pré-Operatório , Proteína Supressora de Tumor p53/sangue , Fatores de Crescimento do Endotélio Vascular/sangue , Linhagem Celular Tumoral , Neoplasias Colorretais/cirurgia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Sensibilidade e Especificidade , Análise de SobrevidaRESUMO
Progression of numerous neoplasms could involve alterations of gap junction channels composed of connexins (Cxs). Disorders of expression and cellular displacement of Cxs were also found in endometrial cancer. Gap junctional intercellular communication can be regulated by wide array of agents, for instance, growth factors, oncogenes, and steroid hormones. Nevertheless, expressions of Cxs and progesterone receptor (PR) were not compared in human tissues. This study focused on assessment of expression of estrogen receptor alpha (ERalpha) and PRs in relation to the expression of Cx26 and Cx43 in 88 cases of endometrial cancer and analysis of these proteins' expression in comparison with anatomoclinical features. Positive ERalpha and PR nuclear staining was present in 66 (75%) and 60 (68.2%) of all studied tumors, respectively. Positive correlation was found between expression of PR and histopathologic type of tumor (P = 0.026), and negative correlation was drawn with grading (G) (P = 0.002). There were positive reactions to Cx26 and Cx43 of mainly cytoplasmic location in 60 (68.2%) and 66 (75%) of studied cancers, respectively. Progesterone receptor expression correlated negatively with Cx26 in endometrial cancers (P = 0.016, r = -0.256). Moreover, ERalpha expression positively correlated with PR expression (P < 0.001, r = 0.678). On the ground of our findings, disorders of Cx expression and altered distribution pattern occur during endometrial carcinogenesis, and it seems that PR could participate in this fact. Loss of functional gap junctions may occur because of the aberrant expression and localization of Cx26 and Cx43 in endometrial cancer.
Assuntos
Carcinoma Endometrioide/metabolismo , Conexina 43/metabolismo , Conexinas/metabolismo , Neoplasias do Endométrio/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/patologia , Estudos de Casos e Controles , Conexina 26 , Neoplasias do Endométrio/patologia , Feminino , Junções Comunicantes/metabolismo , Junções Comunicantes/patologia , Humanos , Pessoa de Meia-Idade , Distribuição TecidualRESUMO
PURPOSE: To reconstruct the biography of the Polish otorhinolaryngologist Leon Zamenhof (1875-1934), a brother of Ludwik Zamenhof, who is famous for invention of the international language Esperanto. METHOD: Biographical information was collected from pre-World War II resources. RESULTS: Zamenhof developed several important new forms of treatment to help the hearing impaired. Zamenhof was especially interested in the education of deaf children and the therapy necessary to facilitate their integration into society. His significant achievements were a phonetic method of therapy for the hearing impaired and an automatic device for ear insufflation that was considered indispensable in the management of pyorrhea. In addition, Zamenhof initiated various forms of social support among physicians within the medical community of Warsaw, Poland; made health care available to children with hearing impairments; and organized a Jewish school for deaf children. Zamenhof tried to change public attitudes toward deafness, working to promote the integration of the deaf into wider society. He also translated Polish literature into Esperanto. CONCLUSIONS: With similar aims to his brother Ludwik, Leon Zamenhof strived to enhance and broaden communication among people who could not hear and to persuade people to change their attitudes about deafness.
Assuntos
Surdez/história , Linguística/história , Otolaringologia/história , Criança , História do Século XIX , História do Século XX , Humanos , PolôniaRESUMO
Adam Zamenhof was greatly influenced by his father, Ludwik Zamenhof, who designed the international language Esperanto. Like his father, he became an ophthalmologist and joined the Esperanto movement. He published in the field of ophthalmology and was soon chosen as head of an ophthalmology department. He subsequently became Chief of the Orthodox Jewish Hospital at Czystem in Warsaw. He was active in the leadership of the Bialystok-Warsaw Chamber of Medical Doctors. He perished in the Nazi Holocaust (Shoah) but all Zamenhof's ideals that Adam served as a doctor and social activist remain still alive.
Assuntos
Oftalmologia/história , Oftalmopatias/história , Oftalmopatias/terapia , História do Século XX , Humanos , Oftalmologia/instrumentação , PolôniaRESUMO
Signal transducer and activator of transcription (STAT3) maintained invasiveness of endometrial cancer cell line. STAT3 mediated signaling for oncogenic growth stimulated by leptin (Ob) and hypoxia-inducible factor 1 (HIF-1). Therefore, we studied STAT3 in relation with HIF-1alpha, Ob, leptin receptor (ObR) and clinical and pathological variables with immunohistochemistry in 48 human endometrioid adenocarcinomas. Nuclear location was a proof of activity of STAT3 and HIF-1 and it was mainly characteristic for granular anti-STAT3 staining and rarely for diffuse HIF-1alpha expression. HIF-1alpha, Ob and ObR presented cytoplasmic granular immunoreactivities. Positive staining for STAT3, HIF-1, Ob and ObR occurred in 75%, 79%, 60% and 31% of cancers, respectively. Anti-STAT3 staining did not significantly vary with grading, staging and patients' age. STAT3 correlated with Ob (p=0.048, r=0.290) and with HIF-1alpha (p=0.004, r=0.407) in all cancers but it failed to associate with ObR at all. In opposition to the absence of significant relationship between STAT3 and Ob, STAT3 correlated with HIF-1alpha in well differentiated cancers (G1), poorly differentiated tumors (G3), pT1b neoplasms, compound group of pT1c, pT2a, pT2b tumors, and older patients over their sixties. STAT3 mediated signaling pathways that engage leptin and HIF-1alpha could only be partially reflected in correlations between STAT3 and Ob or STAT3 and HIF-1alpha in the examined neoplasms. Nevertheless, STAT3 failed to mark cancer advancement, so progressive significance of STAT3 is questionable in endometrioid adenocarcinomas.
Assuntos
Carcinoma Endometrioide/metabolismo , Neoplasias do Endométrio/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Leptina/metabolismo , Receptores para Leptina/metabolismo , Fator de Transcrição STAT3/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Endometrioide/patologia , Núcleo Celular/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-IdadeRESUMO
Erythropoietin via erythropoietin receptor effectively prevents anemia, giving reasons for a clinical use of erythropoietin in patients with colorectal cancers. However, erythropoietin seems to promote survival of the neoplastic cells in hypoxic environment. The aim of this study was to evaluate immunohistochemically the expression of erythropoietin and erythropoietin receptor in 136 primary colorectal cancers with a correlation to different anatomo-clinical features. Erythropoietin correlated with erythropoietin receptor in colorectal cancers (r = 0.547, P < .00001). Erythropoietin and erythropoietin receptor expressions were statistically higher in adenocarcinomas versus mucinous carcinomas (P = .05 and P = .03, respectively) and in moderately (G2) versus poorly differentiated (G3) tumors (P = .001 and P = .02, respectively). This in vivo study is the first study that provides evidences for the presence of erythropoietin and erythropoietin receptor in human colorectal cancer. The expressions of these proteins strictly depended on grading because the better histological differentiation probably comes from trophic influence of erythropoietin and erythropoietin receptor.
Assuntos
Adenocarcinoma Mucinoso/metabolismo , Neoplasias Colorretais/metabolismo , Eritropoetina/metabolismo , Receptores da Eritropoetina/metabolismo , Adenocarcinoma Mucinoso/patologia , Biomarcadores Tumorais/metabolismo , Contagem de Células , Neoplasias Colorretais/patologia , Feminino , Técnica Direta de Fluorescência para Anticorpo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Connexins are integral transmembrane proteins which form specialized hemichannels (connexons) in the plasma membrane. These structures make up gap junctions in adjacent cells which allow for rapid propagation of action potential and slow diffusion of nonorganic ions, secondary messengers, and other small water-soluble molecules (<1.0-2.0 kDa). Connexin proteins are crucial for the formation of gap junctions. Twenty human and 21 murine connexin isoforms (23-64 kDa) have been described so far. Traditional nomenclature in the CxMW format takes into account only the molecular weight of a given connexin. A more recent classification is based on structural gene similarities, their homology and sequence, as well as the length of connexins' cytoplasmic domains. Connexins, as all proteins, have a unique amino-acid sequences and molecular weights and exhibit specific biochemical properties. However, all of them have a common 3-D structure with four hydrophobic transmembrane domains (TM1-TM4), one cytoplasmic (CL) and two extracellular (E1-2) loops, and C- and N-terminal cytoplasmic regions. The cytoplasmic loop and C-terminal regions bind other structural proteins, creating a protein complex crucial for synchronized intercellular communication.
Assuntos
Membrana Celular/metabolismo , Conexinas/química , Conexinas/metabolismo , Animais , Conexinas/classificação , Junções Comunicantes/metabolismo , Humanos , Camundongos , Isoformas de ProteínasRESUMO
BACKGROUND: Leptin is an adipocyte-derived neurohormone, high levels of which are found in obese individuals. Leptin controls energy expenditure, acting in the brain, and regulates different processes in peripheral organs. Recent studies have suggested that leptin may be involved in cancer development and progression. AIMS: To analyse leptin expression in human colorectal cancer as well as in colorectal mucosa and colorectal adenomas. METHODS: Leptin expression was assessed by immunohistochemistry in 166 colorectal cancers, 101 samples of colorectal mucosa and 41 adenomas. Leptin concentration in colorectal cancer was correlated with selected clinicopathological features. RESULTS: Immunoreactivity for leptin was observed in 51.2% (85/166) of primary colorectal cancers. In adenomas leptin expression was observed in 14.6% (6/41) of studied cases. In normal mucosa, leptin was present at low levels, except in tumour bordering areas where its concentration appeared to reflect levels in the adjacent cancer tissue. Leptin expression in colorectal cancer significantly correlated with tumour G2 grade (p = 0.002) as well as with histological type (adenocarcinoma) of tumours (p = 0.044). CONCLUSIONS: Results indicate that leptin is overexpressed in human colorectal cancer, which suggests that the hormone might contribute to colorectal cancer development and progression.
Assuntos
Neoplasias Colorretais/química , Leptina/análise , Adenocarcinoma/química , Adenocarcinoma/patologia , Adenoma/química , Adenoma/patologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Mucosa Intestinal/química , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
Hypoxic cancer cells overexpress Glucose transporter 1 (GLUT-1) to accelerate glucose intake mainly for low effective, anaerobic respiration, so that they would not die of oxygen deficiency. Ischemic cell injury triggers apoptosis. Regulators of cell suicide like Bax and Bcl-xL combine their functions to cause apoptosis or to rescue cells from death. GLUT-1, Bax, and Bcl-xL are of prognostic significance in colorectal cancer but they have not been compared, yet. Thus, we aimed to determine eventual correlations between GLUT-1, Bax, and Bcl-xL in association with different clinicopathological features of colorectal cancer patients. Expressions of the proteins were evaluated in specimens of 150 colorectal patients by immunohistochemistry. The levels of tissue expressions were statistically analyzed with Spearman's correlation test. As in group of all the patients, GLUT-1 matched Bcl-xL and Bax in statistically significant manner regardless of different node status, grade of histological differentiation, histopathological type, tumor site, gender and age of patients. GLUT-1 correlated highly with Bcl-xL in both groups of various tumor growth extent: pT1 + pT2 and pT3 + pT4 tumors (P < 0.016, r = 0.6340, P < 0.0001, r = 0.5204, respectively). Bax correlated with GLUT-1 (P < 0.0001, r = 0.4284) and Bcl-xL (P < 0.0001, r = 0.5233) in pT3 and pT4 tumors without any statistical significance in a homologous comparison at pT1 and pT2 stage (P > 0.173, r = 0.1078, P > 0.744, r = 0.1, respectively). Significant coexpression of GLUT-1, Bcl-xL, and Bax could point to cooperation of these regulatory proteins in elimination due to irreversible injury, adaptation to hypoxia, reduction of further damage, and survival of colorectal cancer cells.
Assuntos
Neoplasias Colorretais/metabolismo , Transportador de Glucose Tipo 1/biossíntese , Proteína X Associada a bcl-2/biossíntese , Proteína bcl-X/biossíntese , Sobrevivência Celular/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Transportador de Glucose Tipo 1/genética , Humanos , Hipóxia/genética , Hipóxia/metabolismo , Proteína X Associada a bcl-2/genética , Proteína bcl-X/genéticaRESUMO
Recent studies suggested that Ob (Ob) and its receptor (ObR) could be involved in the pathogenesis of various human malignancies, among others in endometrial cancer. Moreover, hypoxia, which is associated with solid tumors, might stimulate, through hypoxia-inducible factor 1alpha (HIF-1alpha), expression of Ob and ObR. In this article, we analyzed by immunohistochemistry the expression of Ob, ObR, and HIF-1alpha in 60 cases of human endometrial cancer tissues as well as in 25 cases of normal endometria. Additionally, we assessed correlations among studied proteins as well as relationships with selected clinicopathological features of endometrial cancer. Immunoreactivity for Ob, ObR, and HIF-1alpha protein was observed in 56.7%, 30.0%, and 78.3% of endometrial cancers, respectively. The expression of HIF-1alpha showed a significant positive correlation with Ob (P < 0.0001, r = 0.573) and ObR (P = 0.020, r = 0.299). Moreover, we noted positive correlation between Ob and ObR (P = 0.001, r = 0.429). No statistically significant relationship was revealed between Ob, ObR, and HIF-1alpha protein in regard to patient's age, histological grade, and extent of tumor growth (pT). In conclusion, HIF-1alpha, which is related to tissue hypoxia in endometrial cancer, seems to be associated with overexpression of Ob and ObR. Ob could exert autocrine effect to stimulate endometrial cancer progression. Thus the autocrine Ob loop should be taken into consideration as a novel potential target in endometrial cancer prevention and treatment.
Assuntos
Neoplasias do Endométrio/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Leptina/biossíntese , Receptores de Superfície Celular/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Comunicação Autócrina/genética , Progressão da Doença , Neoplasias do Endométrio/genética , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Leptina/genética , Pessoa de Meia-Idade , Receptores de Superfície Celular/genética , Receptores para LeptinaRESUMO
The aim of the study was the evaluation of ERalpha and ERbeta expression in primary tumors and lymph node metastases of breast cancer as well as the assessment of the influence of preoperative chemotherapy on these receptors with regard to changes in morphological appearance of primary tumors and their metastases. Immunohistochemical examinations were conducted on surgically removed ductal invasive breast cancers and their lymph node metastases of 135 patients. Seventy-one patients were spared preoperative chemotherapy which was administered to other 64 patients. Primary breast cancers with preoperative chemotherapy showed lower mean percentage of cells with a positive reaction to ERalpha and ERbeta as compared to primary tumors without preoperative chemotherapy. There were positive correlations among primary tumors and lymph node metastases regardless of preoperative chemotherapy applied. On the other hand, ERalpha and ERbeta expressions were negatively correlated in primary tumors without chemotherapy in contrast to primary tumors after chemotherapy. Furthermore, it was observed that preoperative chemotherapy was responsible for significantly less damage to lymph node metastases of breast cancer in comparison to primary tumors. In cases of such advanced damage of primary tumors that made determination of estrogen receptor expression impossible, their evaluation was performed on metastases to regional lymph nodes. Although preoperative chemotherapy did not severely impair estrogen receptor expression, presented changes of their distribution are a sufficient reason for simultaneous labeling of estrogen receptors in both primary tumors and metastases due to various sensitivity to chemotherapy of primary cancers in comparison with involved lymph nodes.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor alfa de Estrogênio/biossíntese , Receptor beta de Estrogênio/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células , Receptor alfa de Estrogênio/fisiologia , Receptor beta de Estrogênio/fisiologia , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Pessoa de Meia-Idade , Metástase Neoplásica , PrognósticoRESUMO
The aim of this study was the analysis of Ki-67, Bcl-2 and Bak expression in primary tumor and axillary lymph node metastases of breast cancer as well as an attempt to assess preoperative chemotherapy influence on the mentioned markers with regard to changes in the morphological appearance of the primary tumor and its metastases. Immunohistochemical examinations of Ki-67, Bcl-2 and Bak expression were conducted on sections collected from 135 patients treated surgically on invasive ductal breast cancer. Sixty-four of these patients were administered preoperative chemotherapy, whilst on 71 patients the surgery was performed without initial chemotherapy. In the group of patients without preoperative chemotherapy positive correlation in Ki-67 and Bcl-2 expression between primary tumors and lymph node metastases (p<0.0001, r=0.707; p<0.0001, r=0.604, respectively) was observed. In the group of patients after chemotherapy positive correlation between primary tumors and lymph node metastases in case of Bcl-2 and Bak proteins (p<0.04, r=0.424; p<0.02, r=0.478, respectively) was observed. It was also found that preoperative chemotherapy has an influence on the expression of proteins connected with proliferation and apoptosis and thus, it can influence neoplastic process biology. It does not have any significant impact on the proapoptotic Bak protein expression either in primary tumor or in lymph node metastases of breast cancer. However, it is related to lower expression of antiapoptotic Bcl-2 protein (p<0.0005) and of Ki-67 proliferation marker (p<0.03) in primary tumors, which indirectly indicates a beneficial influence of preoperative chemotherapy on the primary tumor. Concurrently, the influence of neoadjuvant therapy on lymph node metastases seems to be relatively small, which can limit its effectiveness.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Antígeno Ki-67/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/cirurgia , Ciclofosfamida/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , PrognósticoRESUMO
AIMS AND METHODS: Hypoxia-inducible factor (HIF-1) which contains oxygen regulated HIF-1alpha subunit maintains cytoprotective defence against hypoxic injury by induction of numerous genes. However, apoptotic regulators such as Bcl-xL, Bax and P53 have not been associated with HIF-1 dependent regulation in immunohistochemical evaluation of human colorectal cancer tumours so far. Thus, we visualised these proteins immunohistochemically and using Spearman's test compared for the first time their expression in regard to different clinicopathological traits in 123 (113 for P53 evaluation) human colorectal cancers. RESULTS: HIF-1alpha correlated with Bcl-xL or Bax in all patients and particularly in node negative and node positive cancers, deeper intramural tumours (pT3+pT4) and adenocarcinomas. There was no significance in a small group of tumours with lesser extent through intestinal walls (pT1+pT2). In addition HIF-1alpha associated with Bcl-xL in mucinous cancers. Moreover, HIF-1alpha correlated with Bcl-xL or Bax in moderately (G2) and poorly differentiated (G3) cancers, rectal and colonic tumours and in different sex and age groups. P53 correlated only with Bax exclusively in younger patients. CONCLUSIONS: HIF-1alpha may influence expression of Bax or Bcl-xL, at least indirectly, as correlations between HIF-1alpha and Bax or Bcl-xL occur constantly.
Assuntos
Neoplasias Colorretais/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Proteína Supressora de Tumor p53/biossíntese , Proteína X Associada a bcl-2/biossíntese , Proteína bcl-X/biossíntese , Neoplasias Colorretais/patologia , Humanos , Imuno-HistoquímicaRESUMO
PURPOSE: Recent in vitro studies suggested that the autocrine leptin loop might contribute to breast cancer development by enhancing cell growth and survival. To evaluate whether the leptin system could become a target in breast cancer therapy, we examined the expression of leptin and its receptor (ObR) in primary and metastatic breast cancer and noncancer mammary epithelium. We also studied whether the expression of leptin/ObR in breast cancer can be induced by obesity-related stimuli, such as elevated levels of insulin, insulin-like growth factor-I (IGF-I), estradiol, or hypoxic conditions. EXPERIMENTAL DESIGN: The expression of leptin and ObR was examined by immunohistochemistry in 148 primary breast cancers and 66 breast cancer metastases as well as in 90 benign mammary lesions. The effects of insulin, IGF-I, estradiol, and hypoxia on leptin and ObR mRNA expression were assessed by reverse transcription-PCR in MCF-7 and MDA-MB-231 breast cancer cell lines. RESULTS: Leptin and ObR were significantly overexpressed in primary and metastatic breast cancer relative to noncancer tissues. In primary tumors, leptin positively correlated with ObR, and both biomarkers were most abundant in G3 tumors. The expression of leptin mRNA was enhanced by insulin and hypoxia in MCF-7 and MDA-MB-231 cells, whereas IGF-I and estradiol stimulated leptin mRNA only in MCF-7 cells. ObR mRNA was induced by insulin, IGF-I, and estradiol in MCF-7 cells and by insulin and hypoxia in MDA-MB-231 cells. CONCLUSIONS: Leptin and ObR are overexpressed in breast cancer, possibly due to hypoxia and/or overexposure of cells to insulin, IGF-I, and/or estradiol.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Leptina/metabolismo , Obesidade/complicações , Receptores de Superfície Celular/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Estudos de Casos e Controles , Hipóxia Celular , Progressão da Doença , Estradiol/farmacologia , Feminino , Humanos , Insulina/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Leptina/genética , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Obesidade/metabolismo , Receptores de Superfície Celular/genética , Receptores para Leptina , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
HIF-1alpha induces GLUT-1 expression, and their presence has been evaluated in colorectal cancer. However, the expressions of GLUT-1 and HIF-1alpha have not been investigated together with reference to clinicopathological characteristics in human colorectal cancer. The aim of our study was to compare the expression of HIF-1alpha and GLUT-1 with various clinicopathological features of colorectal cancer. The presence of HIF-1alpha and GLUT-1 was visualized immunohistochemically in 123 primary tumors. Membranous localization of GLUT-1 was found in multifocally necrotizing cancer samples, while pure cytoplasmic perinuclear, mostly supranuclear GLUT-1 accumulation was characteristic of cancer fields with lack of necrosis. HIF-1alpha was located in the cytoplasm and occasionally in the nuclei of cancer cells. Immunoreactivity to GLUT-1 was significantly higher in node-positive cancers compared with nodenegative ones (p=0.04), confirming our earlier results obtained on a larger number of patients. Non-mucinous adenocarcinomas expressed GLUT-1 and HIF-1alpha with significantly greater frequency than mucinous adenocarcinomas (p=0.002, p=0.0002, respectively). GLUT-1 and HIF-1alpha expression did not differ in relation to tumor stage, location, or patients' age or gender. In contrast to that of GLUT-1, expression of HIF-1alpha correlated with grade (p=0.00003) without difference with regard to pN status. HIF-1alpha expression correlated with GLUT-1 expression in the whole patient population, as well as in all clinicopathological groups except for the pT1+pT2 group. Although the coexpression of cytoplasmic HIF-1alpha and GLUT-1 does not directly prove the dependence between HIF-1 as a nuclear transcriptional factor and GLUT-1 as its downstream protein, it is evidence of their simultaneous upregulation. The extranuclear accumulation of HIF-1alpha and GLUT-1 requires further studies to explain its significance in colorectal cancer.
Assuntos
Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma/metabolismo , Neoplasias Colorretais/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Neoplasias Colorretais/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
STAT3 upregulates expression of HIF-1 induced EPO. Receptor EPOR was reported to activate STAT3. Our study was aimed at demonstration of tissue immunoreactivities of those proteins and determination of their relationships in reference to clinicopathological variables of breast cancers. We detected STAT3, HIF-1alpha, EPO and EPOR in specimens of 76 human, female, ductal breast cancers by immunohistochemistry. STAT3 was detected in 38 of 76 cancers (50%). HIF-1alpha was found in 55 cases (72%). EPO positive tumors comprised 89% of all the cancers (68 cases). EPOR was also visualized in 55 cases (72%). Anti-HIF-1alpha and anti-STAT3 stained nuclei and cytoplasm of breast cancer cells in diffuse and finely granular fashion. Strong membranous expressions of EPO and EPOR were distributed in cytoplasmic and membranous granularity or diffuse staining. STAT3 correlated with HIF-1 in general (r=0.4012, p<0.0001) and in different patients' subgroups. STAT3 was significantly associated with EPO and EPOR in all the cancers (r=0.2370, p=0.039 and r=0.3336, p=0.003, respectively). Besides a correlation between STAT3 and EPOR in node negative ones, STAT3 wasn't related to EPO and EPOR in remaining subgroups. HIF-1alpha correlated with EPO and EPOR in most of analyzed groups. Immunoreactivity to EPO generally was associated with EPOR (r=0.3520, p=0.002). Statistically analyzed distributions of the proteins reflected functional dependences among STAT3, HIF-1alpha, EPO and EPOR in cellular signal conduction.
Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Eritropoetina/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Receptores da Eritropoetina/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Feminino , HumanosRESUMO
The roles of signal transducers and activators of transcription (STAT) proteins are widely discussed in the pathogenesis of cardiovascular diseases. It is highly probable that STAT1 and STAT3 are activated during proliferation and inflammation inside atheromatous plaques. Luminal surfaces of endothelium become thrombogenic because of STAT1-dependent induction of MHC II and STAT3-regulated recruitment of phospholipase A2. As with STAT1, STAT3 seems to mediate stimulation of vascular wall cells by VEGF, HGF, and Ang II. STAT3 can contribute to counteracting apoptosis by eventual cooperation with c-fos and the bcl-xl gene. As pharmacological agents called statins are reported to regulate activities of STAT proteins, these signal messenger proteins could serve as targets for anti-atherogenic therapy. We attempted to review the role of STAT1 and STAT3 proteins in vascular remodeling.